"Azaspirone" as used herein means a class of polycyclic amine derivatives including, among others, the following azapirones: ##STR1## other 2-pyrimidinyl-1-piperazine derivatives and piperazinylbutylindole derivatives. "Psychogenic symptomatology" as used herein includes, but is not limited to, anxiety, depression, panic disorders, extrapyramidal motor disorders, loss of short term memory, agitation, sexual dysfunction, obsessive-compulsive disorder, anorexia nervosa, premenstrual syndrome, schizophrenia, childhood autism, respiratory stimulation, phencyclidine abuse, nausea and vomiting and the behavior associated with alcohol abuse, drug addiction and nicotine dependence. "Recrystallization" as used herein means the formation of perceptible to visible crystals. "Solubilized" as used herein means the azospirone dissolved in the transdermal delivery system does not recrystallize over time. "Transdermal delivery device", as used herein, means any method of delivering the azospirone across the skin including transdermal delivery devices or the use of creams, ointments, and emollients with the azospirone dissolved or suspended therein.
Azapirones have been shown to be effective for treating a variety of psychogenic symptomatologies. It has been reported that the azapirones act on 5-hydroxytryptaminergic neurons. It is proposed that azapirones act by a general inhibition of serotenergic neurotransmission mediated through activation of 5-hydroxytryptamine.sub.1A receptors of 5-hydroxytryptaminergic neurons. (See New, J.S., "The discovery and development of buspirone: A new approach to the treatment of anxiety", Medicinal Research Reviews 10 (3): 283-326, 1990) Azapirones are effective at low systemic blood concentrations, cause no sedation, and have no known abuse potential. Orally administered azapirones, however, produce irregular blood concentrations and depend on patient compliance for their effectiveness. Therefore, what is needed is a transdermal delivery device that maintains a useful flux of azapirone from the transdermal delivery device for a prolonged period. Such a transdermal delivery devise should enable predictable blood concentrations of azapirone and should rely only minimally on patient compliance to maintain this blood concentration.
The best known of the azapirones, is buspirone. Buspirone is effective in reducing nicotine dependence and in the treatment of, among others, anxiety, depression, panic disorders, extrapyramidal motor disorders, loss of short term memory, agitation, sexual dysfunction, obsessive-compulsive disorder, anorexia nervosa, premenstrual syndrome, schizophrenia, childhood autism, respiratory stimulation, phencyclidine abuse, nausea and vomiting and the behavior associated with alcohol abuse and drug addiction. Each of these psychogenic symptomatologies has been shown clinically to be responsive to oral buspirone. However, orally administered buspirone, is poorly absorbed from the gastrointestinal tract with only 1% to 3% of the oral dose reaching the systemic circulation. In addition, oral buspirone produces irregular blood concentrations and it depends on patient compliance for its effectiveness.
Delivery of certain drugs transdermally has been known to be theoretically possible for many years. Transdermal drug delivery devices are generally laminated composites that include a pressure-sensitive adhesive layer which contains the drug and by which the device is attached to the skin and a backing layer which forms the outer surface of the device and which is impermeable to the drug. To date, only limited commercial exploitation of transdermal drug delivery systems has been achieved, because of the many practical problems to be overcome with real systems. These problems include the solubility of the drug in the adhesive layer, the effect of the drug on the adhesive layer and delivery of the drug to the skin and through the stratum corneum and viable epidermis into the systemic circulation at a constant rate over a prolonged period. In addition, transdermal drug delivery devices should maintain their integrity during long-term storage prior to use.
These problems are particularly difficult to overcome in developing a system for the transdermal delivery of azapirones. First, azapirones are crystalline compounds which should be dissolved before incorporation into the transdermal delivery device. The agents used in the transdermal device not only should dissolve the azapirone, but also should solubilize the dissolved azapirone in the delivery device without compromising the potency of the azapirone. Although azapirones do dissolve in a variety of agents, many of these agents do not solubilize the dissolved azapirone in the adhesive layer. Second, the solubilized azapirone should be compatible with the adhesive layer so it does not effect adversely its adhesive properties. Third, the azapirone should remain solubilized in the delivery device throughout its shelf-life. Fourth, when the transdermal azapirone delivery device is applied to the skin, it should release the azapirone at an effective, steady dose so the flux of solubilized azapirone from the delivery device to the skin and then through the stratum corneum and viable epidermis into the systemic circulation. This flux should be maintained for relatively long periods of time.
Exploitation of the transdermal administration route of azapirones has not been achieved because, although azapirones dissolve in a variety of agents, they have a tendency to recrystallize. Therefore, it is a matter of real difficulty and, to applicants' knowledge, a previously unsolved problem, to find dissolving agents that can solubilize sufficient amounts of azapirones, that do not adversely effect the adhesive layer and that can release the solubilized azapirones in a controlled fashion over a prolonged period.
What is needed is a method of administering buspirone and other azapirones that allows for predictable blood concentrations of the drug for a prolonged period and that relies only minimally on patient compliance.